15-67132695-C-T

Variant names:

• chr15-67132695-C-T
• rs12102171
• NM_005902.4:c.207-32200C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005902.4(SMAD3):​c.207-32200C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,032 control chromosomes in the GnomAD database, including 4,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as confers sensitivity (★).

• Frequency: Genomes: 𝑓 0.23 (4138 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: confers sensitivity criteria provided, single submitter O:1
• Conservation: PhyloP100: -0.995
• Publications: 24 publications found

Genes affected

SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

SMAD3 Gene-Disease associations (from GenCC):

• aneurysm-osteoarthritis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-32200C>T		intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-32200C>T		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34224 AN: 151914 Hom.: 4130 Cov.: 32

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.225 AC: 34259 AN: 152032 Hom.: 4138 Cov.: 32 AF XY: 0.225 AC XY: 16753 AN XY: 74324

African (AFR) AF: 0.299 AC: 12393 AN: 41428

American (AMR) AF: 0.236 AC: 3605 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 925 AN: 3472

East Asian (EAS) AF: 0.347 AC: 1794 AN: 5170

South Asian (SAS) AF: 0.270 AC: 1300 AN: 4818

European-Finnish (FIN) AF: 0.136 AC: 1434 AN: 10576

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12084 AN: 67958

Other (OTH) AF: 0.241 AC: 509 AN: 2110

Alfa AF: 0.193 Hom.: 12961

Bravo AF: 0.237

Asia WGS AF: 0.315 AC: 1094 AN: 3478

ClinVar

Significance: confers sensitivity

Submissions summary: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lung cancer Other:1

May 01, 2012

Kong Lab, Department of Radiation Oncology, Case Western Reserve University School of Medicine

Significance: confers sensitivity

Review Status: criteria provided, single submitter

Collection Method: research

Improve the prediction accuracy for overal survival in non-small cell lung cancer patients -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.61
DANN	Benign	0.27
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12102171; hg19: chr15-67425033;